The present invention relates to a novel process for the preparation of compounds of the general formula 
in which R, R2, R3 and R4 have the meaning below.
Compounds of the formula I are important intermediates for the preparation of pharmaceutically active compounds, for example of HMG-Co A reductase inhibitors. Japanese Patent publication JP-A 06 256318, and Watanabe M. et al., Bioorg. Med. Chem. 1997, Vol. 5, No. 2, 437-444 describe processes for the preparation of compounds of the formula I.
The process described in JP-A 06 256318 has the disadvantage that three stages are needed in order to prepare 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylic acid.
A process for the preparation of ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate has been described by Watanabe M. et al., Bioorg. Med. Chem. 1997, Vol. 5, No. 2, 437-444. In this process, in the first stage p-fluorobenzaldehyde is converted using ethyl iso-butyrylacetate into an unsaturated ketoester, which is then cyclocondensed in the second stage with S-methylisothiourea hydrogensulphate and subsequently dehydrated in the third stage to give the corresponding pyrimidine. In the fourth stage, this is then oxidized using m-chloroperbenzoic acid to give the corresponding sulphonylpyrimidine, which is then reacted in the fifth stage with methylamine and subsequent treatment with methanesulphonyl chloride to give ethyl 4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methyl-amino)pyrimidine-5-carboxylate.
It is disadvantageous in this process, on the one hand, that many reaction stages are necessary and, on the other hand, that the desired product is only formed in moderate yield.
The object of the invention was to make available an economical, industrially feasible process for the preparation of compounds of the formula I.
The object of the invention is achieved by the novel process according to the process of the invention.
According to the invention, compounds of the general formula 
in which
R is hydrogen or a group of the formula xe2x80x94SO2R1;
R1 is C1-6-alkyl;
R2 is hydrogen or C1-6-alkyl;
R3 is C1-6-alkyl;
R4 is C1-6-alkyl,
are prepared in that, in a first stage, a compound of the general formula 
in which R3 and R4 have the abovementioned meaning, is reacted in the presence of a Lewis acid with 4-fluorobenzonitrile to give a compound of the general formula 
in which R3 and R4 have the abovementioned meaning, and in a second stage the compound of the formula III obtained is reacted with a compound of the general formula 
in which R and R2 have the abovementioned meaning, to give the final product of the formula I.
xe2x80x9cC1-6-alkylxe2x80x9d is understood here and below as meaning linear and branched alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, sec-butyl, pentyl and its isomers and hexyl and its isomers.
The compounds of the formula II can be prepared according to Chem. Berichte 1958, 91, 759 or are commercially available organic synthetic chemicals.
4-Fluorobenzonitrile is a commercially available organic synthetic chemical.
The Lewis acid employed in the first stage is expediently an aprotic Lewis acid such as, for example, tin tetrachloride, titanium tetrachloride or aluminium chloride. Tin tetrachloride is preferably employed.
The first stage is expediently carried out in the presence of an organic solvent. The organic solvents employed can be, for example, aromatic hydrocarbons, chlorinated aromatic and aliphatic hydrocarbons. Aromatic hydrocarbons employed are preferably toluene, benzene or xylene. The chlorinated aromatic hydrocarbon employed is preferably chlorobenzene; the chlorinated aliphatic hydrocarbon employed is preferably 1,2-dichloroethane. Toluene and 1,2-dichloroethane are particularly preferably employed.
The reaction in the first stage is expediently carried out at a temperature from xe2x88x925 to 140xc2x0 C., advantageously at 60 to 100xc2x0 C.
After a reaction time of 30 min to 6 h and subsequent hydrolysis, the compounds of the formula III can be isolated by known methods such as, for example, by extraction or can be employed directly, without isolation, for the second stage. The intermediate (formula III) is preferably isolated.
Compounds of the formula III include cis and trans isomers.
In a second stage, a compound of the formula III is reacted with a compound of the formula IV to give the final product of the formula I.
The invention comprises, on the one hand, compounds of the formula I in which R and R2 are hydrogen. These compounds are prepared by reaction of compounds of the formula III with cyanamide.
The reaction with cyanamide is expediently carried out in the presence of an organic solvent, a mixture of water with an organic solvent or in water. Water is particularly preferably employed. Organic solvents employed are advantageously toluene or ethyl acetate. Organic solvents employed as a mixture with water are advantageously alcohols such as, for example, methanol, ethers such as, for example, dioxane or aromatic hydrocarbons such as, for example, toluene or N,N-dimethylacetamide.
The reaction with cyanamide is expediently carried out at a temperature of 10 to 120xc2x0 C., advantageously at 40 to 100xc2x0 C. The pH is expediently in a range from 3 to 9, advantageously in a range from 4 to 7. After a reaction time of, in total, 1 to 20 h, the compounds of the general formula I are obtained, which can be worked up according to known methods.
In a particular embodiment, 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylic acid esters of the general formula 
in which R3 has the meaning indicated in formula I are prepared in that, in a first stage, an alkyl iso-butyrylacetate of the general formula 
in which R3 has the meaning mentioned is reacted in the presence of a Lewis acid with 4-fluorobenzonitrile to give a 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoic acid ester of the general formula 
and in a second stage the compound of the formula IIIa is reacted with cyanamide of the formula 
in which R and R2 are hydrogen, to give the final product of the formula Ia.
The radical R3 is preferably methyl.
The compounds of the formula III are novel and also a subject of the invention.
The invention comprises, on the other hand, compounds of the formula I in which R is a group of the formula xe2x80x94SO2R1 and R1 and R2 are C1-6-alkyl. These 4-(4-fluorophenyl)-6-alkyl-2-(N-alkanesulphonyl-N-alkylamino)pyrimidine-5-carboxylic acid esters of the general formula 
in which R1, R2, R3 and R4 are identical or different and are a C1-6-alkyl group, can be prepared in that 2-[1-amino-1-(4-fluorophenyl)methylene]-4-alkyl-3-oxo-alkanoic acid esters of the general formula 
in which R3 and R4 have the abovementioned meaning, are reacted with N-cyano-N-alkylalkanesulphonamides, optionally isolated or prepared in situ, of the general formula 
in which R1 and R2 are a C1-6-alkyl group.
The reaction can be carried out either in the presence of a base or in the presence of a Lewis acid.
Bases which can be employed are alkali metal compounds such as, for example, alkali metal hydrides, alkali metal carbonates, alkali metal alkoxides or alkali metal silazanes. Alkali metal carbonates which can be used are lithium, sodium or potassium carbonate. The alkali metal hydride employed can be potassium, lithium or sodium hydride; sodium hydride is preferably employed. The alkali metal alkoxide employed can be sodium or potassium tert-pentoxide or sodium or potassium tert-butoxide, preferably sodium tert-pentoxide or sodium tert-butoxide. The alkali metal silazane used can be sodium hexamethyldisilazane or potassium hexamethyldisilazane. The base preferably employed is an alkali metal hydride or an alkali metal alkoxide.
The reaction is expediently carried out in the presence of a base in a polar organic solvent. The polar solvent used can be, for example, N,N-dimethyl-acetamide, isopropanol, tert-butanol, toluene, di-methylformamide, tetrahydrofuran, 1,4-dioxane or mixtures of these. N-Alkylalkanesulphonamides such as, for example, N-methylmethanesulphonamide are likewise suitable as solvents. The reaction is preferably carried out in N-alkylalkanesulphonamide and tert-butanol.
The reaction can be carried out in the presence of a base at a temperature from xe2x88x9210 to 150xc2x0 C., preferably from 0 to 80xc2x0 C.
The reaction of compounds of the formula IIIb with compounds of the formula IVb in the presence of a Lewis acid is expediently carried out in the solvent which is inert to the Lewis acid. Inert solvents which can be employed are, for example, aromatic hydrocarbons, and chlorinated aromatic and aliphatic hydrocarbons. Aromatic hydrocarbons employed are preferably toluene or xylene. The chlorinated aromatic hydrocarbon employed is preferably chlorobenzene; chlorinated aliphatic hydrocarbons employed are preferably dichloromethane or 1,2-dichloroethane.
The reaction in the presence of a Lewis acid can be carried out at a temperature from 20 to 150xc2x0 C., preferably from 80 to 120xc2x0 C.
Suitable Lewis acids are for example TiCl4, TiBr4 or SnCl4. Titanium tetrachloride is preferred.
The amount of Lewis acid is 0.1 to 2 molar equivalents based on the compound of the formula IIIb.
After a reaction time of 1 to 24 h, the final products of the general formula Ib can be isolated by known working-up methods.
In a preferred embodiment, the final product of the formula Ib isolated is ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)-pyrimidine-5-carboxylate (R1=R2=R3=methyl, R4=isopropyl).
Compounds of the formula IVb are expediently prepared in that a compound of the general formula 
in which R1 and R2 are C1-6-alkyl, is reacted with cyanogen halide in the presence of a base.
Suitable bases are the bases described beforehand.
The cyanogen halide employed can be cyanogen fluoride, cyanogen chloride, cyanogen bromide or cyanogen iodide. Cyanogen chloride or cyanogen bromide is preferably employed.
This reaction can likewise be carried out in the polar organic solvents described beforehand. The reaction is preferably carried out in tetrahydrofuran.
The reaction is expediently carried out at a temperature from xe2x88x9220 to 50xc2x0 C., preferably at a temperature from xe2x88x9210 to +20xc2x0 C.
After a reaction time of xc2xe to 1 h, the compounds of the formula IVb, which have not yet been described in the literature, can then be isolated in a manner known to the person skilled in the art.
These compounds of the formula IVb are also a subject of the invention.
Compounds of the formula IVb can be prepared in situ, i.e. they are formed directly from the corresponding starting materials during the reaction without isolation. However, they can also be prepared and isolated separately in order then to employ them for the reaction.
Examples of compounds of the formula IVb are: N-cyano-N-methylmethanesulphonamide, N-cyano-N-ethyl-methanesulphonamide, N-cyano-N-propylmethanesulphonamide, N-cyano-N-butylmethanesulphonamide, N-cyano-N-pentylmethanesulphonamide and N-cyano-N-hexylmethanesulphonamide. N-Cyano-N-methylmethanesulphonamide is preferred.
The compounds of the formula I can also be prepared in that a compound of the general formula 
in which R3 and R4 have the meaning mentioned in claim 1, is reacted with a compound of the formula IV.
The reaction is carried out analogously to the reaction of the compounds of the formula III with compounds of the formula IV, preferably in the presence of a base in a polar organic solvent at a temperature from xe2x88x9210 to 150xc2x0 C.
Suitable bases and solvents correspond to the bases and solvents which are listed under the reaction of compounds of the formula III with compounds of the formula IV.
In a preferred embodiment, compounds of the general formula Ib are prepared in that a compound of the formula VI is reacted with a compound of the formula IVb in a polar organic solvent at a temperature from 0 to 80xc2x0 C. in the presence of a base.
The compounds of the formula VI can be prepared by reaction of C1-6-alkyl nitriles with C1-6-alkyl 4-fluorobenzoylacetate in the presence of a Lewis acid. A compound of the formula VI in which R3 is methyl and R4 is isopropyl is preferred. The Lewis acid is preferably tin tetrachloride. The reaction is expediently carried out in a polar solvent. Suitable solvents correspond to the solvents which are listed under the reaction of compounds of the formula II with compounds of the formula III described above. The reaction in the first stage is expediently carried out at a temperature from xe2x88x925 to 140xc2x0 C., advantageously at 60 to 100xc2x0 C.
The compounds of the formula VI are novel and likewise a subject of the invention.